# US 5,710,286 A · Processes and intermediates for the preparation of cyclic urea HIV protease inhibitors

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- Number: US 5,710,286 A
- Document ID: US5710286A
- Status: Granted
- Kind: A
- Application number: 08/557,254
- Filed: 1995-11-14
- Granted: 1998-01-20
- Earliest claimed: 1994-06-30
- Assignees: The DuPont Merck Pharmaceutical Company
- Inventors: Lucius Thomas Rossano; Young Sek Lo
- Web page: https://patentgrep.com/patent/US5710286A

## CPC

- C07D 491/04: Ortho-condensed systems
- C07D 243/04: having the nitrogen atoms in positions 1 and 3
- C07D 323/00: Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention relates to novel compounds and derivatives thereof containing a trioxepane protected diol in addition to a hydrazone, hydrazine, amine, or cyclic urea moiety; methods for the preparation of said compounds; and the use of said compounds in processes to prepare human immunodeficiency virus (HIV) protease inhibitors which effectively inhibit HIV. The novel compounds provided by this invention have the formulae: ##STR1## wherein the substituents are as defined herein.

## Claims

### Claim 1

The compounds of the formulae: ##STR20## wherein: R.sup.1 and R.sup.2 are independently selected from the group: C.sub.1 -C.sub.4 alkyl, acetyl, phenyl; or R.sup.1 and R.sup.2 may be taken together to form a ring such as triazole, 4-methylpiperazine, or morpholine;
R.sup.4 and R.sup.7 are independently selected from the group:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-3 R.sup.11 or 0-3 R.sup.12 ;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R.sup.12 ;
R.sup.11 and R.sup.11A are independently selected at each occurrence from the group:
H, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --OR.sup.13, --S(O).sub.m R.sup.13, --NR.sup.14 SO.sub.2 NR.sup.13 R.sup.14, --NR.sup.14 SO.sub.2 R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, boronic acid, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, 2-(1-morpholino)ethoxy, azido;
C.sub.3 -C.sub.10 cycloalkyl substituted with 0-2 R.sup.12 ;
C.sub.1 -C.sub.4 alkyl substitued with 0-2 R.sup.12 ;
aryl(C.sub.1 -C.sub.3 alkyl)-, substituted with 0-2 R.sup.12 ;
C.sub.2 -C.sub.6 alkoxyalkyl-, substituted with 0-2 R.sup.12 ;
C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 ;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R.sup.12 ;
R.sup.12, when a substituent on carbon, is independently selected at each occurrence from the group:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.7 -C.sub.10 arylalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.6 cycloalkoxy, --OR.sup.13, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkylene optionally substituted with --Si(CH.sub.3).sub.3, methylenedioxy, ethylenedioxy, --S(O).sub.m R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14, --NHSO.sub.2 R.sup.14, 2-(1-morpholino)ethoxy; or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R.sup.12 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy; or
--NR.sup.13 R.sup.14 ; or
when R.sup.12 is attached to sulfur it may be .dbd.O;
R.sup.12, when a substituent on nitrogen, is independently selected at each occurrence from the group:
phenyl, benzyl, phenethyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl;
R.sup.13 is independently selected at each occurrence from the group:
H;
phenyl substituted with 0-3 R.sup.11A ;
benzyl substituted with 0-3 R.sup.11A ;
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11A ;
an amine protecting group when R.sup.13 is bonded to N;
a hydroxy protecting group when R.sup.13 is bonded to O;
R.sup.14 is independently selected at each occurrence from the group: hydrogen, hydroxy, C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from OH, C.sub.1 -C.sub.4 alkoxy, NH.sub.2, --NH(C.sub.1 -C.sub.4 alkyl), C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyl, phenyl, benzyl, an amine protecting group when R.sup.14 is bonded to N, a hydroxy protecting group when R.sup.14 is bonded to O;
R.sup.13 and R.sup.14 can alternatively join to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
R.sup.13A and R.sup.14A are independently selected at each occurrence from the group: H, C.sub.1 -C.sub.6 alkyl;
R.sup.13A and R.sup.14A can alternatively join to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
R.sup.15 is H or CH.sub.3.

### Claim 2 (depends on 1)

A compound of claim 1 wherein:
R.sup.4 and R.sup.7 are independently selected at each occurrence from the group:
hydrogen;
C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11 ;
C.sub.3 -C.sub.8 cycloalkyl substituted with 0-3 R.sup.11 ;
C.sub.6 -C.sub.10 bicycloalkyl substituted with 0-3 R.sup.11 ;
aryl substituted with 0-3 R.sup.12 ;
a C.sub.6 -C.sub.14 partially unsaturated carbocyclic residue substituted with 0-3 R.sup.12 ;
a 5- to 6-membered heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R.sup.12.

### Claim 3 (depends on 1)

A compound of claim 1 wherein:
R.sup.4 and R.sup.7 are independently selected at each occurrence from the group:
hydrogen;
C.sub.1 -C.sub.4 alkyl substituted with 0-3 R.sup.11 ;
R.sup.11 is independently selected at each occurrence from the group:
H, cyano, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, --OR.sup.13, C.sub.2 -C.sub.4 alkoxyalkyl, --S(O).sub.m R.sup.13, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.10 cycloalkyl;
a C.sub.5 -C.sub.14 saturated or partially unsaturated carbocyclic residue substituted with 0-3 R.sup.12 ;
aryl(C.sub.1 -C.sub.3 alkyl)-substituted with 0-2 R.sup.12 ;
aryl substituted with 0-3 R.sup.12 ; or
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R.sup.12 ;
R.sup.12 when a substituent on carbon, is independently selected at each occurrence from the group:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, C.sub.7 -C.sub.10 arylalkyl, C.sub.1 -C.sub.4 alkoxy, 2-(1-morpholino)ethoxy, C.sub.3 -C.sub.6 cycloalkoxy, --OR.sup.13, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, --S(O).sub.m R.sup.13, --SO.sub.2 NR.sup.13 R.sup.14 ; or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R.sup.12 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, or --NR.sup.13 R.sup.14 ; or when R.sup.12 is attached to sulfur it may be .dbd.O;
R.sup.12, when a substituent on nitrogen, is independently selected at each occurrence from the group:
phenyl, benzyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, --CH.sub.2 NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, C.sub.2 -C.sub.6 alkoxyalkyl;
R.sup.13 is independently selected at each occurrence from the group: H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkoxyalkyl, phenyl, or benzyl;
R.sup.14 is independently selected at each occurrence from the group: OH, H, CF.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, NH.sub.2, phenyl, or benzyl;
R.sup.13 and R.sup.14 can alternatively join to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --.

### Claim 4 (depends on 1)

The compounds of claim 1 wherein:
R.sup.4 and R.sup.7 are independently selected at each occurrence from the group: benzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyl, or naphthylmethyl;
R.sup.4 and R.sup.7 are both benzyl, isobutyl, 4-nitrobenzyl, 4-fluorobenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-hydroxybenzyl, 4-(2-hydroxyethoxy)benzyl, 4-(2-morpholinylethoxy)benzyl, 3-(H.sub.2 NC(.dbd.O)CH.sub.2 O)benzyl, 3,4-difluorobenzyl, 2-naphthylmethyl, 2-thienylmethyl, 4-methylthiobenzyl, isopropyl, or 4-pyridylmethyl;
R.sup.4 is 4-nitrobenzyl and R.sup.7 is 2-nitrobenzyl;
and
R.sup.4 is 4-aminobenzyl and R.sup.7 is 2-aminobenzyl.